Phosphorylation of Smooth Muscle 22 Alpha Facilitates Angiotensin II-Inducted ROS Production via Activation of PKCδ-P47phox Axis Through Release of PKCδ and Actin Dynamics and Is Associated with Hypertrophy and Hyperplasia of Vascular Smooth Muscle Cells in Vitro and in Vivo.

MedLine Citation:

PMID:
22798525
Owner:
NLM
Status:
Publisher

Abstract/OtherAbstract:

Rationale: We have demonstrated that SM22α inhibits cell proliferation via blocking Ras-ERK1/2 signaling in vascular smooth muscle cells (VSMCs) and in injured arteries. The recent study indicates that SM22α disruption can independently promote arterial inflammation through activation of ROS-mediated NF-κB pathways. However, the mechanisms by which SM22α controls ROS production have not been characterized. Objective: To investigate how SM22α disruption promotes ROS production and to characterize the underlying mechanisms. Methods and Results: ROS level was measured by dihydroethidium (DHE) staining for superoxide and TBA assay for malondialdehyde (MDA), respectively. We showed that down-regulation and phosphorylation of SM22α were associated with angiotensin (Ang) II-induced increase in ROS production in VSMCs of rats and human. Ang II induced the phosphorylation of SM22α at Serine 181 in an AT1R-PKCδ pathway-dependent manner. Phosphorylated SM22α activated PKCδ-p47phox axis via two distinct pathways: 1) disassociation of PKCδ from SM22α, and in turn binding to p47phox, in early stage of Ang II stimulation; 2) acceleration of SM22α degradation through ubiquitin-proteasome, enhancing PKCδ membrane translocation via induction of actin cytoskeletal dynamics in later oxidative stress. Inhibition of SM22α phosphorylation abolished Ang II-activated PKCδ-p47phox axis, and inhibited the hypertrophy and hyperplasia of VSMCs in vitro and in vivo, accompanied with reduction of ROS generation.Conclusions: These findings indicate that the disruption of SM22α plays pivotal roles in vascular oxidative stress. PKCδ-mediated SM22α phosphorylation is a novel link between actin cytoskeletal remodeling and oxidative stress and may be a potential target for the development of new therapeutics for cardiovascular diseases.